Abstract 519: Clinical impact of<i>KRAS</i>G12, G13, Q61, K117 and A146 mutations in patients with colorectal liver metastases
Authors: Iris van 't Erve, Nina J. Wesdorp, Jamie E. Medina, Leonardo Ferreira, Alessandro Leal, Joost Huiskens, Karen Bolhuis, Jan-Hein T. van Waesberghe, Rutger-Jan Swijnenburg, Daan van den Broek, Victor E. Velculescu, Geert Kazemier, Cornelis J. Punt, Gerrit A. Meijer, Remond J. Fijneman
Journal: Cancer Research (2022)

Abstract Introduction: The distribution of KRAS mutation variants across tumor types is not uniform. The KRAS A146 mutation is predominantly seen in colorectal cancer (CRC) patients. Here, we evaluated how clinical features like tumor load and overall survival differ between metastatic CRC (mCRC) patients carrying distinct somatic KRAS G12, G13, Q61, K117 or A146 mutations. Methods: 419 CRC patients with initially unresectable liver-limited metastases, who participated in the multicenter CAIRO5 prospective clinical trial, were evaluated for tumor tissue KRAS mutation status. For the subgroup of patients who carried a KRAS mutation and were treated with bevacizumab and doublet or triplet chemotherapy (N=156), clinical outcome was evaluated and pretreatment tumor burden was quantified as liquid biopsy circulating tumor DNA (ctDNA) mutant allele fraction (MAF) and as total tumor volume (TTV) on CT imaging. The MAF, TTV and overall survival were compared between patients harboring different KRAS mutation variants. Results: Of the 156 patients with a KRAS mutated tumor, most carried a KRAS G12 mutation (N=112, 71.8%), followed by mutations in G13 (N=15, 9.6%), A146 (N=12, 7.7%), Q61 (N=9, 5.8%) and K117 (N=5, 3.2%). High plasma ctDNA levels were observed for patients carrying a KRAS A146 mutation versus those with a KRAS G12 mutation, with a median MAF of 48% versus 19%, respectively. Radiological TTV revealed this difference to be associated with a higher tumor load in patients harboring a KRAS A146 mutation (median TTV 672 cm3 (A146) versus 74 cm3 (G12), p=0.036). Moreover, KRAS A146 mutation carriers showed inferior overall survival compared to patients with mutations in KRAS G12 (median 10.7 versus 26.4 months; HR=2.5; p=0.003), and the multivariable Cox regression analysis showed that the KRAS alteration was the only independent prognostic factor for overall survival. Conclusion and Relevance: This study revealed that within mCRC patients A146 is the third most common KRAS mutation variant, and mCRC patients carrying a KRAS A146 mutation represent a distinct molecular subtype of patients with high tumor burden and poor clinical outcome. This highlights the importance of testing CRC for all KRAS mutations in routine clinical care and shows the opportunity for personalized treatment beyond detecting the presence of a KRAS mutation by taking the specific KRAS mutation variant into account. Citation Format: Iris van 't Erve, Nina J. Wesdorp, Jamie E. Medina, Leonardo Ferreira, Alessandro Leal, Joost Huiskens, Karen Bolhuis, Jan-Hein T. van Waesberghe, Rutger-Jan Swijnenburg, Daan van den Broek, Victor E. Velculescu, Geert Kazemier, Cornelis J. Punt, Gerrit A. Meijer, Remond J. Fijneman. Clinical impact ofKRASG12, G13, Q61, K117 and A146 mutations in patients with colorectal liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 519.